Forkhead Domains of FOXO Transcription Factors Differ in both Overall Conformation and Dynamics

0510048 - FGÚ 2020 RIV CH eng J - Článek v odborném periodiku
Pšenáková, Katarína - Kohoutová, K. - Obšilová, Veronika - Ausserlechner, M. J. - Veverka, Václav - Obšil, Tomáš
Forkhead Domains of FOXO Transcription Factors Differ in both Overall Conformation and Dynamics.
Cells. Roč. 8, č. 9 (2019), č. článku 966. E-ISSN 2073-4409
Grant CEP: GA ČR GF17-33854L; GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:67985823 ; RVO:61388963
Klíčová slova: FOXO1 * Forkhead domain * structure * DNA-binding domain * nuclear magnetic resonance
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 4.366, rok: 2019
Způsob publikování: Open access
https://doi.org/10.3390/cells8090966

FOXO transcription factors regulate cellular homeostasis, longevity and response to stress. FOXO1 (also known as FKHR) is a key regulator of hepatic glucose production and lipid metabolism, and its specific inhibition may have beneficial effects on diabetic hyperglycemia by reducing hepatic glucose production. Moreover, all FOXO proteins are considered potential drug targets for drug resistance prevention in cancer therapy. However, the development of specific FOXO inhibitors requires a detailed understanding of structural differences between individual FOXO DNA-binding domains. The high-resolution structure of the DNA-binding domain of FOXO1 reported in this study and its comparison with structures of other FOXO proteins revealed differences in both their conformation and flexibility. These differences are encoded by variations in protein sequences and account for the distinct functions of FOXO proteins. In particular, the positions of the helices H1, H2 and H3, whose interface form the hydrophobic core of the Forkhead domain, and the interactions between hydrophobic residues located on the interface between the N-terminal segment, the H2-H3 loop, and the recognition helix H3 differ among apo FOXO1, FOXO3 and FOXO4 proteins. Therefore, the availability of apo structures of DNA-binding domains of all three major FOXO proteins will support the development of FOXO-type-specific inhibitors.
Trvalý link: http://hdl.handle.net/11104/0300612